The overall goal of this research is to understand the mechanisms of maternal immune tolerance to the fetus in pregnancy. The intimacy between the maternal immune system and the fetal allograft is an unparalleled physiological situation in which antigenically unique, tissue-specific proteins are introduced to the mothers immune system for the first time at the commencement and for the duration of pregnancy. The Aire gene encodes a transcriptional regulator that induces tissue-specific gene expression in the thymus, such that tolerance to these antigens is ensured in developing thymocytes. The studies proposed herein explore the novel hypothesis that the thymus expresses these antigens, and that this expression, as mediated by Aire, is necessary for immune tolerance to the fetus. The Specific Aims of this project are: 1. Determine whether the fetus and/or placenta are targets of maternal immunity in Aire- deficient mice. 2. Examine the developmental regulation of gestation-associated antigens in the human and murine thymus. Few studies have directly addressed the role of the thymus in maternal-fetal tolerance - a surprising gap in our knowledge, considering the well known role of this organ in tolerance to self antigens. The experiments outlined here will thus yield ground-breaking insights into the mechanisms of maternal- fetal tolerance as well as autoimmune disease, and in turn, new implications for therapeutic intervention of immune-mediated disease will arise. PUBLIC HEALTH RELEVANCE: Numerous medical situations arise from either inappropriate immune tolerance to antigens, such as those associated with cancer cells, or inappropriate immune intolerance, such as that of failed pregnancy, autoimmune disease, and rejection of transplanted tissue. Pregnancy represents a perfect balance of coexistence between a foreign "graft" and the maternal immune system, which adapts to promote the growth of the fetus rather than reject it. Understanding the events surrounding this unique physiological situation will yield insight on how infertility, cancer and autoimmune disease may be alleviated.